Heavy Metals Toxicity: Mechanism, Health Effects, and Therapeutic Interventions

Abstract

Heavy metals (HMs), such as chromium, arsenic, cadmium, mercury, and lead, constitute a class of environmental pollutants with significant toxicity that pose a serious threat to human health. This review provides a comprehensive overview of the biochemical properties of HMs, and their effects at the cellular, molecular, and genetic levels. HMs exert their toxic effects by interfering with various intracellular biochemical processes, including enzyme activity, protein synthesis, and energy metabolism. Furthermore, they can disrupt the integrity of cell membranes and affect cellular signaling, leading to cellular dysfunction and death. At the molecular and genetic levels, HMs can cause DNA damage and induce gene mutations, thereby affecting genetic transmission and expression. Then, the effects of HMs on the nervous system, kidneys, cardiovascular system, reproduction, and cancer risk are discussed. Therapeutic strategies, such as chelation therapy, antioxidants and free radical scavengers, supportive therapy, and prevention and reduction of exposure, have been shown to mitigate the toxic effects of HMs. Last, based on the current findings on the mechanisms of HMs, future research directions are prospected. Through multidisciplinary cooperation and integrated interventions, it is expected that the health risks posed by HMs can be alleviated. Future research needs to further elucidate the mechanisms of HMs toxicity, develop more effective treatments, and strengthen preventive and control measures.

Keywords

disease / heavy metal toxicity / mechanism / therapeutic intervention

References

[1] F. Dragan, M. Lestyan, V. V. Lupu, et al., “The Threat of Mercury Poisoning by Fish Consumption,” Applied Sciences 13 (2023): 369.

[2] L. Cilliers and F. Retief, “Chapter 14-Lead Poisoning and the Downfall of Rome: Reality or Myth?” Toxicology in Antiquity (Second Edition) (2019), 221-229.

[3] J. McCurry, “Japan remembers Minamata,” Lancet 9505 (2006): 99-100.

[4] X. Zhou, Q. Wang, and X. Yang, “[Progresses on mechanisms of pharmacological and toxicological effects of cinnabar],” Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica 34, no. 22 (2009): 2843-2847.

[5] C. J. Chen, S. K. Wu, Y. B. Wang, J. F. Hou, L. Ma, and X. Y. Sun, “[Recent Researches of Synthetic mercury Sulfide in Traditional Medicine System],” Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica 37, no. 19 (2012): 2968-2970.

[6] Y. Zhao, B. Yuan, K. Onda, et al., “Anticancer Efficacies of Arsenic Disulfide Through Apoptosis Induction, Cell Cycle Arrest, and Pro-Survival Signal Inhibition in Human Breast Cancer Cells,” American Journal of Cancer Research 8, no. 3 (2018): 366-386.

[7] L. Wei, R. Xue, P. Zhang, Y. Wu, X. Li, and F. Pei, “(1)H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated With Cinnabar, a Traditional Chinese Medicine,” Omics : a Journal of Integrative Biology 19 (2015): 490-498.

[8] Z. Xiang, S. Wu, L. Zhu, K. Yang, D. Lin, “Pollution Characteristics and Source Apportionment of Heavy Metal(loid)s in Soil and Groundwater of a Retired Industrial Park,” Journal of Environmental Sciences 143 (2024): 23-34.

[9] D. Zhao, P. Wang, and F. J. Zhao, “Toxic Metals and Metalloids in Food: Current Status, Health Risks, and Mitigation Strategies,” Current Environmental Health Reports 11 (2024): 468-483.

[10] H. Ali and E. Khan, “What are Heavy Metals? Long-Standing Controversy Over the Scientific use of the Term ‘Heavy Metals’ - Proposal of a Comprehensive Definition,” Toxicological & Environmental Chemistry 100 (2018): 6-19.

[11] K. Jomova, S. Y. Alomar, E. Nepovimova, K. Kuca, and M. Valko, “Heavy Metals: Toxicity and Human Health Effects,” Archives of Toxicology 99 (2025): 153-209.

[12] T. J. van der Kuijp, L. Huang, and C. R. Cherry, “Health Hazards of China's Lead-Acid Battery Industry: A Review of its Market Drivers, Production Processes, and Health Impacts,” Environmental Health : a Global Access Science Source 12 (2013): 61.

[13] A. Rashid, B. J. Schutte, A. Ulery, et al., “Heavy Metal Contamination in Agricultural Soil: Environmental Pollutants Affecting Crop Health,” Agronomy 13 (2023): 1521.

[14] M. Adnan, B. Xiao, M. U. Ali, et al., “Heavy Metals Pollution From Smelting Activities: A Threat to Soil and Groundwater,” Ecotoxicology and Environmental Safety 274 (2024): 116189.

[15] X. Ma, Z. Sha, Y. Li, et al., “Temporal-Spatial Characteristics and Sources of Heavy Metals in Bulk Deposition Across China,” The Science of the Total Environment 926 (2024): 171903.

[16] C. Li, X. Zhang, M. Dong, X. Han, “Progress on Crowding Effect in Cell-Like Structures,” Membranes 12 (2022): 593.

[17] C. Wang, P. Zou, C. Yang, et al., “Dynamic Modifications of biomacromolecules: Mechanism and Chemical Interventions,” Science China Life Sciences 62 (2019): 1459-1471.

[18] A. VonHandorf, H. A. Zablon, and A. Puga, “Hexavalent Chromium Disrupts Chromatin Architecture,” Seminars in Cancer Biology 76 (2021): 54-60.

[19] S.-G. Park and D. Butcher, “Investigation of the Interaction Between Arsenic Species and Thiols via Electrospray Ionization Tandem Mass Spectrometry,” Microchemical Journal 95 (2010): 57-66.

[20] S. Shila, M. Subathra, and M. A. Devi, C. Panneerselvam, “Arsenic Intoxication-Induced Reduction of Glutathione Level and of the Activity of Related Enzymes in rat Brain Regions: Reversal by DL-Alpha-Lipoic Acid,” Archives of Toxicology 79 (2005): 140-146.

[21] C. A. Vergara-Gerónimo, A. León Del Río, M. Rodríguez-Dorantes, P. Ostrosky-Wegman, and A. M. Salazar, “Arsenic-Protein Interactions as a Mechanism of Arsenic Toxicity,” Toxicology and Applied Pharmacology 431 (2021): 115738.

[22] S. S. Katti and T. I. Igumenova, “Protein-Cadmium Interactions in Crowded Biomolecular Environments Probed by In-cell and Lysate NMR Spectroscopy,” Biorxiv (2024): 2023.11.03.565546

[23] S. A. Rupa, M. A. M. Patwary, M. M. Matin, W. E. Ghann, J. Uddin, and M. Kazi, “Interaction of Mercury Species With Proteins: Towards Possible Mechanism of Mercurial Toxicology,” Toxicology Research 12 (2023): 355-368.

[24] M. J. Warren, J. B. Cooper, S. P. Wood, and P. M. Shoolingin-Jordan, “Lead Poisoning, Haem Synthesis and 5-Aminolaevulinic Acid Dehydratase,” Trends in Biochemical Sciences 23 (1998): 217-221.

[25] T. L. DesMarais and M. Costa, “Mechanisms of Chromium-Induced Toxicity,” Current Opinion in Toxicology 14 (2019): 1-7.

[26] Y. Hu, J. Li, B. Lou, et al., “The Role of Reactive Oxygen Species in Arsenic Toxicity,” Biomolecules 10 (2020): 240.

[27] F. Qu and W. Zheng, “Cadmium Exposure: Mechanisms and Pathways of Toxicity and Implications for Human Health,” Toxics 12 (2024): 388.

[28] J. Albrecht, E. Matyja, “Glutamate: A Potential Mediator of Inorganic Mercury Neurotoxicity,” Metabolic Brain Disease 11 (1996): 175-184.

[29] V. Matović, A. Buha, D. Ðukić-Ćosić, and Z. Bulat, “Insight Into the Oxidative Stress Induced by Lead and/or Cadmium in Blood, Liver and Kidneys,” Food and Chemical Toxicology 78 (2015): 130-140.

[30] A. Samborska, Z. Stepniewska, and W. Stepniewski, “Influence of Different Oxidation States of Chromium (VI, III) on Soil Urease Activity,” Geoderma 122 (2004): 317-322.

[31] S. Ran, X. Gao, M. Ma, et al., “NaAsO2 Decreases GSH Synthesis by Inhibiting GCLC and Induces Apoptosis Through Hela cell Mitochondrial Damage, Mediating the Activation of the NF-κB/miR-21 Signaling Pathway,” Ecotoxicology and Environmental Safety 234 (2022): 113380.

[32] O. I. Oluranti, E. A. Agboola, N. E. Fubara, M. O. Ajayi, and O. S. Michael, “Cadmium Exposure Induces Cardiac Glucometabolic Dysregulation and Lipid Accumulation Independent of Pyruvate Dehydrogenase Activity,” Annals of Medicine 53 (2021): 1108-1117.

[33] B. Fernandes Azevedo, L. Barros Furieri, F. M. Peçanha, et al., “Toxic Effects of Mercury on the Cardiovascular and Central Nervous Systems,” Journal of Biomedicine & Biotechnology 2012 (2012): 949048.

[34] C. Wang, H. Shang, S. Zhang, et al., “Hexavalent Chromium Disrupts the Skin Barrier by Targeting ROS-Mediated Mitochondrial Pathway Apoptosis in Keratinocytes,” Chemico-Biological Interactions 379 (2023): 110523.

[35] W. Guo, D. Li, Y. Zhai, et al., “Differential Interaction Modes of As(III)/As(V) With Microbial cell Membrane Induces Opposite Effects on Organic Contaminant Biodegradation in Groundwater,” Environment International 193 (2024): 109074.

[36] E. Van Kerkhove, V. Pennemans, and Q. Swennen, “Cadmium and Transport of Ions and Substances Across cell Membranes and Epithelia,” Biometals 23 (2010): 823-855.

[37] R. Notariale, E. Längst, P. Perrone, D. Crettaz, M. Prudent, and C. Manna, “Effect of Mercury on Membrane Proteins, Anionic Transport and Cell Morphology in Human Erythrocytes,” Cellular Physiology and Biochemistry 56 (2022): 500-513.

[38] M. B. Dlamini, Z. Gao, Hasenbilige, et al., “The Crosstalk Between Mitochondrial Dysfunction and Endoplasmic Reticulum Stress Promoted ATF4-Mediated Mitophagy Induced by Hexavalent Chromium,” Environmental Toxicology 36 (2021): 1162-1172.

[39] C. Prakash and V. Kumar, “Arsenic-Induced Mitochondrial Oxidative Damage is Mediated by Decreased PGC-1α Expression and its Downstream Targets in rat Brain,” Chemico-Biological Interactions 256 (2016): 228-235.

[40] J. J. V. Branca, A. Pacini, M. Gulisano, N. Taddei, C. Fiorillo, and M. Becatti, “Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain,” Frontiers in Cell and Developmental Biology 8 (2020): 604377.

[41] J. Y. Lee, G. W. Hwang, A. Naganuma, and M. Satoh, “Methylmercury Toxic Mechanism Related to Protein Degradation and Chemokine Transcription,” Environmental Health and Preventive Medicine 25 (2020): 30.

[42] M. Chlubek and I. Baranowska-Bosiacka, “Selected Functions and Disorders of Mitochondrial Metabolism Under Lead Exposure,” Cells 13 (2024): 1182.

[43] Y. Ma, S. Li, S. Tang, et al., “Clusterin Protects Against Cr(VI)-Induced Oxidative Stress-Associated Hepatotoxicity by Mediating the Akt-Keap1-Nrf2 Signaling Pathway,” Environmental Science and Pollution Research International 29 (2022): 52289-52301.

[44] C. C. Lin, C. S. Pan, C. Y. Wang, S. W. Liu, L. D. Hsiao, and C. M. Yang, “Tumor Necrosis Factor-Alpha Induces VCAM-1-Mediated Inflammation via c-Src-Dependent Transactivation of EGF Receptors in Human Cardiac Fibroblasts,” Journal of Biomedical Science 22 (2015): 53.

[45] C. Y. Zhang, A. J. Ou, L. Jin, et al., “Cadmium Exposure Triggers Alveolar Epithelial cell Pyroptosis by Inducing Mitochondrial Oxidative Stress and Activating the cGAS-STING Pathway,” Cell Communication and Signaling 22 (2024): 566.

[46] S. H. Kim and R. P. Sharma, “Mercury-Induced Apoptosis and Necrosis in Murine Macrophages: Role of Calcium-Induced Reactive Oxygen Species and p38 Mitogen-Activated Protein Kinase Signaling,” Toxicology and Applied Pharmacology 196 (2004): 47-57.

[47] J. Guo, R. Li, Z. Ouyang, et al., “Insights Into the Mechanism of Transcription Factors in Pb2+-Induced Apoptosis,” Toxicology 503 (2024): 153760.

[48] Z. Fang, M. Zhao, H. Zhen, L. Chen, P. Shi, and Z. Huang, “Genotoxicity of Tri- and Hexavalent Chromium Compounds In Vivo and Their Modes of Action on DNA Damage In Vitro,” PLoS ONE 9 (2014): e103194.

[49] X. Zhou, R. M. Speer, L. Volk, L. G. Hudson, and K. J. Liu, “Arsenic Co-Carcinogenesis: Inhibition of DNA Repair and Interaction With Zinc Finger Proteins,” Seminars in Cancer Biology 76 (2021): 86-98.

[50] M. Filipic, T. Fatur, and M. Vudrag, “Molecular Mechanisms of Cadmium Induced Mutagenicity,” Human & Experimental Toxicology 25 (2006): 67-77.

[51] L. H. Wyatt, A. L. Luz, X. Cao, et al., “Effects of Methyl and Inorganic Mercury Exposure on Genome Homeostasis and Mitochondrial Function in Caenorhabditis Elegans,” Dna Repair 52 (2017): 31-48.

[52] S. Hemmaphan and N. K. Bordeerat, “Genotoxic Effects of Lead and Their Impact on the Expression of DNA Repair Genes,” International Journal of Environmental Research and Public Health 19 (2022): 4307.

[53] Z. Wang, Z. Liu, P.-S. Wang, et al., “Epigenetic Downregulation of O6-Methylguanine-DNA Methyltransferase Contributes to Chronic Hexavalent Chromium Exposure-Caused Genotoxic Effect and Cell Transformation,” Environmental Pollution 341 (2024): 122978.

[54] M. Iyer, U. Anand, S. Thiruvenkataswamy, et al., “A Review of Chromium (Cr) Epigenetic Toxicity and Health Hazards,” The Science of the Total Environment 882 (2023): 163483.

[55] Y. Qin, H. Xu, Y. Xi, et al., “Effects of the SEMA4B Gene on Hexavalent Chromium [Cr(VI)]-Induced Malignant Transformation of Human Bronchial Epithelial Cells,” Toxicology Research 13 (2024): tfae030.

[56] T. F. Cheng, S. Choudhuri, and K. Muldoon-Jacobs, “Epigenetic Targets of Some Toxicologically Relevant Metals: A Review of the Literature,” Journal of Applied Toxicology 32 (2012): 643-653.

[57] Z. Xing and B. P. Tu, “Mechanisms and Rationales of SAM Homeostasis,” Trends in Biochemical Sciences 50 (2025): 242-254.

[58] H. Li, L. Wu, F. Ye, et al., “As3MT via Consuming SAM is Involved in Arsenic-Induced Nonalcoholic Fatty Liver Disease by Blocking m6A-Mediated miR-142-5p Maturation,” The Science of the Total Environment 892 (2023): 164746.

[59] N. F. Fitz, A. Barchowsky, R. Koldamova, and I. Lefterov, “Genome-Wide Alteration of Histone Methylation Profiles Associated With Cognitive Changes in Response to Developmental Arsenic Exposure in Mice,” Toxicology Reports 9 (2022): 393-403.

[60] S. Hu, A. Song, L. Peng, et al., “H3K4me2/3 Modulate the Stability of RNA Polymerase II Pausing,” Cell Research 33 (2023): 403-406.

[61] V. Hure, F. Piron-Prunier, T. Yehouessi, et al., “Alternative Silencing States of Transposable Elements in Arabidopsis Associated With H3K27me3,” Genome biology 26 (2025): 11.

[62] S. Frings, R. Schmidt-Schippers, and W.-K. Lee, “Epigenetic Alterations in Bioaccumulators of Cadmium: Lessons From Mammalian Kidneys and Plants,” Environment International 191 (2024): 109000.

[63] A. H. Guo, S. Kumar, and D. B. Lombard, “Epigenetic Mechanisms of Cadmium-Induced Nephrotoxicity,” Current Opinion in Toxicology 32 (2022): 100372.

[64] T. Ke, A. A. Tinkov, A. V. Skalny, et al., “Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence From Experimental Studies,” Toxics 11 (2023): 72.

[65] G. Bjørklund, L. Pivina, M. Dadar, Y. Semenova, S. Chirumbolo, and J. Aaseth, “Mercury Exposure, Epigenetic Alterations and Brain Tumorigenesis: A Possible Relationship?,” Current Medicinal Chemistry 27 (2020): 6596-6610.

[66] M. Luo, Y. Xu, R. Cai, et al., “Epigenetic Histone Modification Regulates Developmental Lead Exposure Induced Hyperactivity in Rats,” Toxicology Letters 225 (2014): 78-85.

[67] S. Ceryak, C. Zingariello, T. O'Brien, and S. R. Patierno, “Induction of Pro-Apoptotic and Cell Cycle-Inhibiting Genes in Chromium (VI)-Treated Human Lung Fibroblasts: Lack of Effect of ERK,” Molecular and Cellular Biochemistry 255 (2004): 139-149.

[68] X. Xiong, Y. Li, L. Liu, et al., “Arsenic Trioxide Induces Cell Cycle Arrest and Affects Trk Receptor Expression in Human Neuroblastoma SK-N-SH Cells,” Biological Research 51 (2018): 18.

[69] V. Selvaraj, M. Y. Armistead, M. Cohenford, and E. Murray, “Arsenic Trioxide (As(2)O(3)) Induces Apoptosis and Necrosis Mediated Cell Death Through Mitochondrial Membrane Potential Damage and Elevated Production of Reactive Oxygen Species in PLHC-1 Fish Cell Line,” Chemosphere 90 (2013): 1201-1209.

[70] D. Ospondpant, S. Phuagkhaopong, K. Suknuntha, et al., “Cadmium Induces Apoptotic Program Imbalance and Cell Cycle Inhibitor Expression in Cultured Human Astrocytes,” Environmental Toxicology and Pharmacology 65 (2019): 53-59.

[71] I. Pellarin, A. Dall'Acqua, A. Favero, et al., “Cyclin-Dependent Protein Kinases and Cell Cycle Regulation in Biology and Disease,” Signal Transduction and Targeted Therapy 10 (2025): 11.

[72] B. Kang, J. Wang, and S. Guo, L. Yang, “Mercury-Induced Toxicity: Mechanisms, Molecular Pathways, and Gene Regulation,” The Science of the Total Environment 943 (2024): 173577.

[73] C. G. Yedjou, “Tchounwou PB: DNA Damage, Cell Cycle Arrest, and Apoptosis Induction Caused by Lead in Human Leukemia Cells,” International Journal of Environmental Research and Public Health 13 (2015): ijerph13010056.

[74] M. Ahamed and M. K. Siddiqui, “Low Level Lead Exposure and Oxidative Stress: Current Opinions,” Clinica Chimica Acta 383 (2007): 57-64.

[75] A. Chamoli and S. K. Karn, “, The Effects of Mercury Exposure on Neurological and Cognitive Dysfunction in Human: A Review,” in Mercury Toxicity Mitigation: Sustainable Nexus Approach. ed. N. Kumar (Springer Nature Switzerland, 2024): 117-135.

[76] P. Deng, H. Zhang, L. Wang, et al., “Long-Term Cadmium Exposure Impairs Cognitive Function by Activating lnc-Gm10532/m6A/FIS1 Axis-Mediated Mitochondrial Fission and Dysfunction,” The Science of the Total Environment 858 (2023): 159950.

[77] S. R. Fan, T. T. Ren, M. Y. Yun, R. Lan, and X. Y. Qin, “Edaravone Attenuates Cadmium-Induced Toxicity by Inhibiting Oxidative Stress and Inflammation in ICR Mice,” Neurotoxicology 86 (2021): 1-9.

[78] F. Xu, S. Farkas, S. Kortbeek, F. X. Zhang, L. Chen, and G. W. Zamponi, “Syed NI: Mercury-Induced Toxicity of rat Cortical Neurons is Mediated Through N-Methyl-D-Aspartate Receptors,” Molecular Brain 5 (2012): 30.

[79] A. H. Rezvani, “Involvement of the NMDA System in Learning and Memory,” In: Edited by ED Levin, JJ Buccafusco (CRC Press/Taylor & Francis, 2006).

[80] V. Karri, M. Schuhmacher, and V. Kumar, “Heavy Metals (Pb, Cd, As and MeHg) as Risk Factors for Cognitive Dysfunction: A General Review of Metal Mixture Mechanism in Brain,” Environmental Toxicology and Pharmacology 48 (2016): 203-213.

[81] G. G. Kovacs, “Concepts and Classification of Neurodegenerative Diseases,” Handbook of Clinical Neurology 145 (2017): 301-307.

[82] I. Y. Iskusnykh, A. A. Zakharova, E. D. Kryl'skii, and T. N. Popova, “Aging, Neurodegenerative Disorders, and Cerebellum,” International Journal of Molecular Sciences 25 (2024): 1018.

[83] G. S. Bloom, “Amyloid-β and tau: The Trigger and Bullet in Alzheimer Disease Pathogenesis,” JAMA Neurology 71 (2014): 505-508.

[84] L. Stefanis, “α-Synuclein in Parkinson's Disease,” Cold Spring Harbor Perspectives in Medicine 2 (2012): a009399.

[85] E. Feneberg, E. Gray, O. Ansorge, K. Talbot, and M. R. Turner, “Towards a TDP-43-Based Biomarker for ALS and FTLD,” Molecular Neurobiology 55 (2018): 7789-7801.

[86] C. A. Ross and S. J. Tabrizi, “Huntington's Disease: From Molecular Pathogenesis to Clinical Treatment,” The Lancet Neurology 10 (2011): 83-98.

[87] K. Panchal and A. K. Tiwari, “Mitochondrial Dynamics, a Key Executioner in Neurodegenerative Diseases,” Mitochondrion 47 (2019): 151-173.

[88] S. A. Wolf, H. W. Boddeke, and H. Kettenmann, “Microglia in Physiology and Disease,” Annual Review of Physiology 79 (2017): 619-643.

[89] M. Lv, X. Ma, K. Zhang, et al., “The Disruption of Blood-Brain Barrier Induced by Long-Term Arsenic Exposure is Associated With the Increase of MMP-9 and MMP-2: The Characteristics are Similar to Those Caused by Senescence,” Chemico-Biological Interactions 385 (2023): 110743.

[90] T. Zhou, Z. Huang, X. Sun, et al., “Microglia Polarization With M1/M2 Phenotype Changes in rd1 Mouse Model of Retinal Degeneration,” Frontiers in Neuroanatomy 11 (2017): 77.

[91] J. A. Ansari, S. K. Mishra, R. K. Dey, et al., “Minocycline Reverses Developmental Arsenic Exposure-Induced Microglia Activation and Functional Alteration in BALB/c Mice,” Environmental Toxicology and Pharmacology 92 (2022): 103858.

[92] R. Sharma, M. D. Abubakar, P. Bisht, et al., “Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease,” Current Molecular Pharmacology (2023)

[93] M. A. Rahman, M. A. Hannan, M. J. Uddin, M. S. Rahman, M. M. Rashid, and B. Kim, “Exposure to Environmental Arsenic and Emerging Risk of Alzheimer's Disease: Perspective Mechanisms, Management Strategy, and Future Directions,” Toxics 9 (2021): 188.

[94] A. Chakraborty, S. Ghosh, B. Biswas, S. Pramanik, J. Nriagu, and S. Bhowmick, “Epigenetic Modifications From Arsenic Exposure: A Comprehensive Review,” The Science of the Total Environment 810 (2022): 151218.

[95] J. Y. Min and K. B. Min, “Blood Cadmium Levels and Alzheimer's Disease Mortality Risk in Older US Adults,” Environmental Health : a Global Access Science Source 15 (2016): 69.

[96] T. Ali, A. Khan, S. I. Alam, et al., “Cadmium, an Environmental Contaminant, Exacerbates Alzheimer's Pathology in the Aged Mice's Brain,” Frontiers in Aging Neuroscience 13 (2021): 650930.

[97] J. Del Pino, G. Zeballos, M. J. Anadón, et al., “Cadmium-Induced Cell Death of Basal Forebrain Cholinergic Neurons Mediated by Muscarinic M1 Receptor Blockade, Increase in GSK-3β Enzyme, β-Amyloid and Tau Protein Levels,” Archives of Toxicology 90 (2016): 1081-1092.

[98] T. Kimura, K. Ishiguro, and S. Hisanaga, “Physiological and Pathological Phosphorylation of Tau by CDK5,” Frontiers in Molecular Neuroscience 7 (2014): 65.

[99] S. Phuagkhaopong, D. Ospondpant, T. Kasemsuk, et al., “Cadmium-Induced IL-6 and IL-8 Expression and Release From Astrocytes are Mediated by MAPK and NF-κB Pathways,” Neurotoxicology 60 (2017): 82-91.

[100] R. Siblerud, J. Mutter, E. Moore, J. Naumann, and H. Walach, “A Hypothesis and Evidence That Mercury May be an Etiological Factor in Alzheimer's Disease,” International Journal of Environmental Research and Public Health 16 (2019): 5152.

[101] L. Behzadfar, S. Hassani, H. Feizpour, et al., “Effects of Mercuric Chloride on Spatial Memory Deficit-Induced by Beta-Amyloid and Evaluation of Mitochondrial Function Markers in the Hippocampus of Rats,” Metallomics : Integrated Biometal Science 12 (2020): 144-153.

[102] C. C. Zhou, Z. Y. Gao, J. Wang, et al., “Lead Exposure Induces Alzheimers's Disease (AD)-Like Pathology and Disturbes Cholesterol Metabolism in the Young Rat Brain,” Toxicology Letters 296 (2018): 173-183.

[103] J. Wu, M. R. Basha, B. Brock, et al., “Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys After Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD,” The Journal of Neuroscience 28 (2008): 3-9.

[104] A. Ashok, N. K. Rai, S. Tripathi, and S. Bandyopadhyay, “Exposure to As-, Cd-, and Pb-Mixture Induces Aβ, Amyloidogenic APP Processing and Cognitive Impairments via Oxidative Stress-Dependent Neuroinflammation in Young Rats,” Toxicological Sciences 143 (2015): 64-80.

[105] P. Srivastava, Y. K. Dhuriya, R. Gupta, et al., “Protective Effect of Curcumin by Modulating BDNF/DARPP32/CREB in Arsenic-Induced Alterations in Dopaminergic Signaling in Rat Corpus Striatum,” Molecular Neurobiology 55 (2018): 445-461.

[106] M. Golpich, E. Amini, F. Hemmati, et al., “Glycogen Synthase Kinase-3 Beta (GSK-3β) Signaling: Implications for Parkinson's Disease,” Pharmacological Research 97 (2015): 16-26.

[107] Y. Xu, H. Hong, X. Lin, et al., “Chronic Cadmium Exposure Induces Parkinson-Like Syndrome by Eliciting Sphingolipid Disturbance And Neuroinflammation in the Midbrain of C57BL/6J Mice,” Environmental Pollution 337 (2023): 122606.

[108] A. N. Tsentsevitsky and A. M. Petrov, “Synaptic Mechanisms of Cadmium Neurotoxicity,” Neural Regeneration Research 16 (2021): 1762-1763.

[109] S. B. Mimouna, M. Chemek, S. Boughammoura, M. Banni, and I. Messaoudi, “Early-Life Exposure to Cadmium Triggers Distinct Zn-Dependent Protein Expression Patterns and Impairs Brain Development,” Biological Trace Element Research 184 (2018): 409-421.

[110] R. Pamphlett and D. P. Bishop, “Mercury is Present in Neurons and Oligodendrocytes in Regions of the Brain Affected by Parkinson's Disease and Co-Localises With Lewy Bodies,” PLoS ONE 17 (2022): e0262464.

[111] V. Matović, A. Buha, D. Ðukić-Ćosić, and Z. Bulat, “Insight Into the Oxidative Stress Induced by Lead and/or Cadmium in Blood, Liver and Kidneys,” Food and Chemical Toxicology 78 (2015): 130-140.

[112] J. T. Rogers, V. Venkataramani, C. Washburn, et al., “A Role for Amyloid Precursor Protein Translation to Restore Iron Homeostasis and Ameliorate Lead (Pb) Neurotoxicity,” Journal of Neurochemistry 138 (2016): 479-494.

[113] J. Zhang, T. Cai, F. Zhao, et al., “The Role of α-Synuclein and Tau Hyperphosphorylation-Mediated Autophagy and Apoptosis in Lead-Induced Learning and Memory Injury,” International Journal of Biological Sciences 8 (2012): 935-944.

[114] V. Gupta, N. G. Ansari, R. K. Garg, and S. Khattri, “Determination of Cd, Cr, Pb and Ni Contents Among Parkinson's Disease Individuals: A Case-Control Study,” The International Journal of Neuroscience 127 (2017): 770-775.

[115] K. Rezaei, G. Mastali, E. Abbasgholinejad, et al., “Cadmium Neurotoxicity: Insights Into Behavioral Effect and Neurodegenerative Diseases,” Chemosphere 364 (2024): 143180.

[116] M. Forcella, P. Lau, M. Oldani, et al., “Neuronal Specific and Non-Specific Responses to Cadmium Possibly Involved in Neurodegeneration: A Toxicogenomics Study in a Human Neuronal Cell Model,” Neurotoxicology 76 (2020): 162-173.

[117] B. Xu, S. Chen, Y. Luo, et al., “Calcium Signaling is Involved in Cadmium-Induced Neuronal Apoptosis via Induction of Reactive Oxygen Species and Activation of MAPK/mTOR Network,” PLoS ONE 6 (2011): e19052.

[118] Y. Yuan, C. Y. Jiang, H. Xu, et al., “Cadmium-Induced Apoptosis in Primary rat Cerebral Cortical Neurons Culture is Mediated by a Calcium Signaling Pathway,” PLoS ONE 8 (2013): e64330.

[119] Y. H. Huang, C. M. Shih, C. J. Huang, et al., “Effects of Cadmium on Structure and Enzymatic Activity of Cu,Zn-SOD and Oxidative Status in Neural Cells,” Journal of Cellular Biochemistry 98 (2006): 577-589.

[120] A. Prasad, V. Bharathi, V. Sivalingam, A. Girdhar, and B. K. Patel, “Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis,” Frontiers in Molecular Neuroscience 12 (2019): 25.

[121] E. Minj, S. Upadhayay, and S. Mehan, “Nrf2/HO-1 Signaling Activator Acetyl-11-Keto-Beta Boswellic Acid (AKBA)-Mediated Neuroprotection in Methyl Mercury-Induced Experimental Model of ALS,” Neurochemical Research 46 (2021): 2867-2884.

[122] P. E. A. Ash, U. Dhawan, S. Boudeau, et al., “Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology,” Toxicological Sciences 167 (2019): 105-115.

[123] A. Shandilya, S. Mehan, S. Kumar, et al., “Activation of IGF-1/GLP-1 Signalling via 4-Hydroxyisoleucine Prevents Motor Neuron Impairments in Experimental ALS-Rats Exposed to Methylmercury-Induced Neurotoxicity,” Molecules (Basel, Switzerland)27 (2022): 3878.

[124] M. R. Vargas, M. Pehar, P. J. Díaz-Amarilla, J. S. Beckman, and L. Barbeito, “Transcriptional Profile of Primary Astrocytes Expressing ALS-Linked Mutant SOD1,” Journal of Neuroscience Research 86 (2008): 3515-3525.

[125] L. C. Wijesekera and P. N. Leigh, “Amyotrophic Lateral Sclerosis,” Orphanet Journal of Rare Diseases 4 (2009): 3.

[126] A. Chiò, A. Calvo, L. Mazzini, et al., “Extensive Genetics of ALS: A Population-Based Study in Italy,” Neurology 79 (2012): 1983-1989.

[127] M. S. Rotunno, D. A. Bosco, “An Emerging Role for Misfolded Wild-Type SOD1 in Sporadic ALS Pathogenesis,” Frontiers in Cellular Neuroscience 7 (2013): 253.

[128] D. R. Rosen, T. Siddique, D. Patterson, et al., “Mutations in Cu/Zn Superoxide Dismutase Gene are Associated With Familial Amyotrophic Lateral Sclerosis,” Nature 362 (1993): 59-62.

[129] P. J. Kamitsuka, M. M. Ghanem, R. Ziar, S. E. McDonald, M. G. Thomas, and G. F. Kwakye, “Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells,” International Journal of Molecular Sciences 24 (2023): 7178.

[130] G. F. Kwakye, J. A. Jiménez, M. G. Thomas, et al., “Heterozygous Huntingtin Promotes Cadmium Neurotoxicity and Neurodegeneration in Striatal Cells via Altered Metal Transport and Protein Kinase C Delta Dependent Oxidative Stress and Apoptosis Signaling Mechanisms,” Neurotoxicology 70 (2019): 48-61.

[131] Y. H. Wu, J. C. Lin, T. Y. Wang, et al., “Hexavalent Chromium Intoxication Induces Intrinsic and Extrinsic Apoptosis in Human Renal Cells,” Molecular Medicine Reports 21 (2020): 851-857.

[132] B. A. Fowler, “14-Arsenical Kidney Toxicity,” Handbook of Arsenic Toxicology (2023): 395-408.

[133] S. Satarug, “Is Chronic Kidney Disease Due to Cadmium Exposure Inevitable and Can It Be Reversed?” Biomedicines 12 (2024): 718.

[134] Y. Rbaibi, K. R. Long, K. E. Shipman, et al., “Megalin, Cubilin, and Dab2 Drive Endocytic Flux in Kidney Proximal Tubule Cells,” Molecular Biology of the Cell 34 (2023): ar74.

[135] X. Wang, L. Han, G. Li, et al., “From the Cover: Identification of Natural Products as Inhibitors of Human Organic Anion Transporters (OAT1 and OAT3) and Their Protective Effect on Mercury-Induced Toxicity,” Toxicological Sciences 161 (2018): 321-334.

[136] C. C. Bridges and R. K. Zalups, “The Aging Kidney and the Nephrotoxic Effects of Mercury,” Journal of Toxicology and Environmental Health Part B, Critical Reviews 20 (2017): 55-80.

[137] R. K. Zalups, “Molecular Interactions With Mercury in the Kidney,” Pharmacological Reviews 52 (2000): 113-143.

[138] M. N. Rana, J. Tangpong, and M. M. Rahman, “Toxicodynamics of Lead, Cadmium, Mercury and Arsenic- Induced Kidney Toxicity and Treatment Strategy: A Mini Review,” Toxicology Reports 5 (2018): 704-713.

[139] C. V. Nolan and Z. A. Shaikh, “Lead Nephrotoxicity and Associated Disorders: Biochemical Mechanisms,” Toxicology 73 (1992): 127-146.

[140] Z. Pan, T. Gong, and P. Liang, “Heavy Metal Exposure and Cardiovascular Disease,” Circulation Research 134 (2024): 1160-1178.

[141] M. C. Sanguinetti, C. Jiang, M. E. Curran, and M. T. Keating, “A Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG Encodes the IKr Potassium Channel,” Cell 81 (1995): 299-307.

[142] J. L. Mumford, K. Wu, Y. Xia, et al., “Chronic Arsenic Exposure and Cardiac Repolarization Abnormalities With QT Interval Prolongation in a Population-Based Study,” Environmental Health Perspectives 115 (2007): 690-694.

[143] X. Cao, S. Wang, R. Bi, S. Tian, Y. Huo, and J. Liu, “Toxic Effects of Cr(VI) on the Bovine Hemoglobin and Human Vascular Endothelial Cells: Molecular Interaction and Cell Damage,” Chemosphere 222 (2019): 355-363.

[144] G. Choong, Y. Liu, and D. M. Templeton, “Interplay of Calcium and Cadmium in Mediating Cadmium Toxicity,” Chemico-Biological Interactions 211 (2014): 54-65.

[145] M. T. Nelson, “Interactions of Divalent Cations With Single Calcium Channels From Rat Brain Synaptosomes,” Journal of General Physiology 87 (1986): 201-222.

[146] N. B. Lemos, J. K. Angeli, O. Faria Tde, et al., “Low Mercury Concentration Produces Vasoconstriction, Decreases Nitric Oxide Bioavailability and Increases Oxidative Stress in Rat Conductance Artery,” PLoS ONE 7 (2012): e49005.

[147] Z. W. Hu, R. Kerb, X. Y. Shi, T. Wei-Lavery, and B. B. Hoffman, “Angiotensin II Increases Expression of Cyclooxygenase-2: Implications for the Function of Vascular Smooth Muscle Cells,” The Journal of Pharmacology and Experimental Therapeutics 303 (2002): 563-573.

[148] T. O. Faria, M. R. Simões, D. V. Vassallo, et al., “Xanthine Oxidase Activation Modulates the Endothelial (Vascular) Dysfunction Related to HgCl(2) Exposure Plus Myocardial Infarction in Rats,” Cardiovascular Toxicology 18 (2018): 161-174.

[149] N. D. Vaziri, “Mechanisms of Lead-Induced Hypertension and Cardiovascular Disease,” American Journal of Physiology. Heart and Circulatory Physiology 295 (2008): H454-465.

[150] J. J. Wellings, J. M. Thorpe, K. Yendole, Y. Matsubayashi, and P. S. Hartley, “Effect of Short and Long-Term Cadmium Exposure on Behaviour and Cardiac Function in Drosophila,” Environmental Pollution (Barking, Essex : 1987) 366 (2025): 125481.

[151] M. L. Fitch, R. Kabir, O. V. Ebenebe, et al., “Cadmium Exposure Induces a Sex-Dependent Decline in Left Ventricular Cardiac Function,” Life Sciences 324 (2023): 121712.

[152] Q. Liu, C. Xu, J. Jin, et al., “Early-Life Exposure to Lead Changes Cardiac Development and Compromises Long-Term Cardiac Function,” The Science of the Total Environment 904 (2023): 166667.

[153] G. Ferreira de Mattos, C. Costa, F. Savio, M. Alonso, and G. L. Nicolson, “Lead Poisoning: Acute Exposure of the Heart to Lead Ions Promotes Changes in Cardiac Function and Cav1.2 ion Channels,” Biophysical Reviews 9 (2017): 807-825.

[154] R. Balakrishnan, C. S. Kumar, M. U. Rani, K. Kavita, G. Boobalan, and A. G. Reddy, “Evaluation of Protective Action of α-Tocopherol in Chromium-Induced Oxidative Stress in Female Reproductive System of Rats,” Journal of Natural Science, Biology and Medicine 4 (2013): 87-93.

[155] A. K. Chandra, A. Chatterjee, R. Ghosh, and M. Sarkar, “Effect of Curcumin on Chromium-Induced Oxidative Damage in Male Reproductive System,” Environmental Toxicology and Pharmacology 24 (2007): 160-166.

[156] P. Chen, Q. Luo, Y. Lin, et al., “Arsenic Exposure During Juvenile and Puberty Significantly Affected Reproductive System Development of Female SD Rats,” Ecotoxicology and Environmental Safety 242 (2022): 113857.

[157] S. Mitra, S. Bhattacharyya, S. Ray, et al., “Resveratrol Alleviates Cadmium-Induced Damage and Overexpression of Epidermal Growth Factor Receptor and its Downstream Signaling Proteins in the Reproductive System of Male Swiss Albino Mice,” Journal of Environmental Pathology, Toxicology and Oncology 35 (2016): 73-90.

[158] S. Li, B. Han, P. Wu, et al., “Effect of Inorganic Mercury Exposure on Reproductive System of male Mice: Immunosuppression and Fibrosis in Testis,” Environmental Toxicology 37 (2022): 69-78.

[159] M. M. Ommati, H. N. Ahmadi, S. Sabouri, et al., “Glycine Protects the Male Reproductive System Against Lead Toxicity via Alleviating Oxidative Stress, Preventing Sperm Mitochondrial Impairment, Improving Kinematics of Sperm, and Blunting the Downregulation of Enzymes Involved in the Steroidogenesis,” Environmental Toxicology 37 (2022): 2990-3006.

[160] P. Jacquet and J. P. Draye, “Toxicity of Chromium Salts to Cultured Mouse Embryos,” Toxicology Letters 12 (1982): 53-57.

[161] C. Zhang, C. Liu, D. Li, et al., “Intracellular Redox Imbalance and Extracellular Amino Acid Metabolic Abnormality Contribute to Arsenic-Induced Developmental Retardation in Mouse Preimplantation Embryos,” Journal of Cellular Physiology 222 (2010): 444-455.

[162] J. Zhu, Z. Huang, F. Yang, et al., “Cadmium Disturbs Epigenetic Modification and Induces DNA Damage in Mouse Preimplantation Embryos,” Ecotoxicology and Environmental Safety 219 (2021): 112306.

[163] W. Yu, Y. Tu, Z. Long, et al., “Reactive Oxygen Species Bridge the Gap Between Chronic Inflammation and Tumor Development,” Oxidative Medicine and Cellular Longevity 2022 (2022): 2606928.

[164] L. Zhao, R. Islam, Y. Wang, X. Zhang, and L. Z. Liu, “Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis,” Cancers 14 (2022): 5768.

[165] Z. Feng, W. Hu, W. N. Rom, M. Costa, and M. S. Tang, “Chromium(VI) Exposure Enhances Polycyclic Aromatic Hydrocarbon-DNA Binding at the p53 Gene in Human Lung Cells,” Carcinogenesis 24 (2003): 771-778.

[166] C. Ren, Y. Zhou, W. Liu, and Q. Wang, “Paradoxical Effects of Arsenic in the Lungs,” Environmental Health and Preventive Medicine 26 (2021): 80.

[167] R. Hubaux, D. D. Becker-Santos, K. S. Enfield, S. Lam, W. L. Lam, and V. D. Martinez, “Arsenic, Asbestos and Radon: Emerging Players in Lung Tumorigenesis,” Environmental Health 11 (2012): 89.

[168] R. J. Person, E. J. Tokar, Y. Xu, R. Orihuela, N. N. Ngalame, and M. P. Waalkes, “Chronic Cadmium Exposure in Vitro Induces Cancer Cell Characteristics in Human Lung Cells,” Toxicology and Applied Pharmacology 273 (2013): 281-288.

[169] C. L. Siewit, B. Gengler, E. Vegas, R. Puckett, and M. C. Louie, “Cadmium Promotes Breast Cancer Cell Proliferation by Potentiating the Interaction Between ERalpha and c-Jun,” Molecular Endocrinology (Baltimore, Md) 24 (2010): 981-992.

[170] X. Yu, E. J. Filardo, and Z. A. Shaikh, “The Membrane Estrogen Receptor GPR30 Mediates Cadmium-Induced Proliferation of Breast Cancer Cells,” Toxicology and Applied Pharmacology 245 (2010): 83-90.

[171] G. Furtak, M. Kozłowski, S. Kwiatkowski, and A. Cymbaluk-Płoska, “The Role of Lead and Cadmium in Gynecological Malignancies,” Antioxidants (Basel, Switzerland) 11 (2022): 2468.

[172] A. Stoica, B. S. Katzenellenbogen, and M. B. Martin, “Activation of Estrogen Receptor-Alpha by the Heavy Metal Cadmium,” Molecular Endocrinology (Baltimore, Md) 14 (2000): 545-553.

[173] C. P. Pineda-Belmontes, R. U. Hernández-Ramírez, C. Hernández-Alcaraz, M. E. Cebrián, and L. López-Carrillo, “Genetic Polymorphisms of PPAR Gamma, Arsenic Methylation Capacity and Breast Cancer Risk in Mexican Women,” Salud Publica De Mexico 58 (2016): 220-227.

[174] J. D. Davis and S. Y. Lin, “DNA Damage and Breast Cancer,” World Journal of Clinical Oncology 2 (2011): 329-338.

[175] A. Nersesyan, M. Kundi, M. Waldherr, et al., “Results of Micronucleus Assays With Individuals Who Are Occupationally and Environmentally Exposed to Mercury, Lead and Cadmium,” Mutation Research Reviews in Mutation Research 770 (2016): 119-139.

[176] W. Qu, H. Ke, J. Pi, et al., “Acquisition of Apoptotic Resistance in Cadmium-Transformed Human Prostate Epithelial Cells: BCL-2 Overexpression Blocks the Activation of JNK Signal Transduction Pathway,” Environmental Health Perspectives 115 (2007): 1094-1100.

[177] L. Benbrahim-Tallaa and M. P. Waalkes, “Inorganic Arsenic and Human Prostate Cancer,” Environmental Health Perspectives 116 (2008): 158-164.

[178] L. Benbrahim-Tallaa, R. A. Waterland, M. Styblo, W. E. Achanzar, M. M. Webber, and M. P. Waalkes, “Molecular Events Associated With Arsenic-Induced Malignant Transformation of Human Prostatic Epithelial Cells: Aberrant Genomic DNA Methylation and K-Ras Oncogene Activation,” Toxicology and Applied Pharmacology 206 (2005): 288-298.

[179] M. Sun, Z. Jiang, P. Gu, et al., “Cadmium Promotes Colorectal Cancer Metastasis Through EGFR/Akt/mTOR Signaling Cascade and Dynamics,” The Science of the Total Environment 899 (2023): 165699.

[180] Z. Zhang, H. Cao, N. Song, L. Zhang, Y. Cao, and J. Tai, “Long-Term Hexavalent Chromium Exposure Facilitates Colorectal Cancer in Mice Associated With Changes in Gut Microbiota Composition,” Food and Chemical Toxicology 138 (2020): 111237.

[181] M. Zemelka-Wiacek, “The Interaction Among Effector, Regulatory, and Tγδ Cells Determines the Development of Allergy or Tolerance to Chromium,” Journal of Clinical Medicine 14 (2025): 1370.

[182] Q. Qian, P. Li, T. Wang, et al., “Alteration of Th1/Th2/Th17 Cytokine Profile and Humoral Immune Responses Associated With Chromate Exposure,” Occupational and Environmental Medicine 70 (2013): 697-702.

[183] L. N. Islam: 21-An Update on the Immunotoxic Effects of Arsenic Exposure. Handbook of Arsenic Toxicology 2nd Edn. In: Edited by Flora SJS. (Oxford: Academic Press, 2023): 551-592.

[184] I. Mirkov, A. Popov Aleksandrov, and M. Ninkov, “Immunotoxicology of Cadmium: Cells of the Immune System as Targets and Effectors of Cadmium Toxicity,” Food and Chemical Toxicology 149 (2021): 112026.

[185] N. Pathak and S. Khandelwal, “Impact of Cadmium in T Lymphocyte Subsets and Cytokine Expression: Differential Regulation by Oxidative Stress and Apoptosis,” Biometals 21 (2008): 179-187.

[186] K. M. Pollard, D. M. Cauvi, C. B. Toomey, P. Hultman, and D. H. Kono, “Mercury-Induced Inflammation and Autoimmunity,” Biochimica Et Biophysica Acta General Subjects 1863 (2019): 129299.

[187] U. Undeger, N. Başaran, H. Canpinar, and E. Kansu, “Immune Alterations in Lead-Exposed Workers,” Toxicology 109 (1996): 167-172.

[188] M. E. Sears, “Chelation: Harnessing and Enhancing Heavy Metal Detoxification-A Review,” The Scientific World Journal 2013 (2013): 219840.

[189] İ. Gulcin and S. H. Alwasel, “Metal Ions, Metal Chelators and Metal Chelating Assay as Antioxidant Method,” Processes 10 (2022): 132.

[190] W. Wu, L. Chen, W. Zhang, and D. Mei, “Comparison of Heavy Metal Contaminants Removal Using EDTA and Cyanex 302 as Chelating Agents for Supercritical CO2-Based Soil Remediation,” Chemical Engineering Research and Design 206 (2024): 130-138.

[191] T. George and M. F. Brady, “Ethylenediaminetetraacetic Acid (EDTA),” StatPearls. (StatPearls Publishing, 2023).

[192] G. Bjørklund, G. Crisponi, V. M. Nurchi, R. Cappai, A. Buha Djordjevic, and J. Aaseth, “A Review on Coordination Properties of Thiol-Containing Chelating Agents Towards Mercury, Cadmium, and Lead,” Molecules (Basel, Switzerland) 24 (2019): 3247.

[193] A. Kovács, D. S. Nemcsok, and T. Kocsis, “Bonding Interactions in EDTA Complexes,” Journal of Molecular Structure 950 (2010): 93-97.

[194] R. A. Goyer, M. G. Cherian, M. M. Jones, and J. R. Reigart, “Role of Chelating Agents for Prevention, Intervention, and Treatment of Exposures to Toxic Metals,” Environmental Health Perspectives 103 (1995): 1048-1052.

[195] J. Aaseth, M. A. Skaug, Y. Cao, and O. Andersen, “Chelation in Metal Intoxication-Principles and Paradigms,” Journal of Trace Elements in Medicine and Biology 31 (2015): 260-266.

[196] M. J. Kosnett, “The Role of Chelation in the Treatment of Arsenic and Mercury Poisoning,” Journal of Medical Toxicology 9 (2013): 347-354.

[197] M. B. Sulzberger, R. L. Baer, and A. Kanof, “Clinical Uses of 2,3-Dimercaptopropanol (BAL); Studies on the Toxicity of BAL on Percutaneous and Parenteral Administration,” The Journal of Clinical Investigation 25 (1946): 474-479.

[198] R. A. Peters, “Development and Theoretical Significance of British Anti-Lewisite,” British Medical Bulletin 5 (1948): 313-319.

[199] O. Andersen, “Principles and Recent Developments in Chelation Treatment of Metal Intoxication,” Chemical Reviews 99 (1999): 2683-2710.

[200] M. J. Kosnett: BAL (DIMERCAPROL). Poisoning & Drug Overdose. 7e edn. In: Edited by Olson KR, Anderson IB, Benowitz NL, Blanc PD, Clark RF, Kearney TE, Kim-Katz SY, Wu AHB (McGraw-Hill Education, 2018).

[201] S. Bradberry and A. Vale, “Dimercaptosuccinic Acid (Succimer; DMSA) in Inorganic Lead Poisoning,” Clin Toxicol (Phila) 47 (2009): 617-631.

[202] A. L. Miller, “Dimercaptosuccinic Acid (DMSA), a Non-Toxic, Water-Soluble Treatment for Heavy Metal Toxicity,” Alternative Medicine Review 3 (1998): 199-207.

[203] H. V. Aposhian, R. M. Maiorino, R. C. Dart, and D. F. Perry, “Urinary Excretion of Meso-2,3-Dimercaptosuccinic Acid in Human Subjects,” Clinical Pharmacology & Therapeutics 45 (1989): 520-526.

[204] V. Gersl, R. Hrdina, J. Vávrová, et al., “Effects of Repeated Administration of Dithiol Chelating Agent-Sodium 2,3-Dimercapto-1-Propanesulphonate (DMPS)-On Biochemical and Haematological Parameters in Rabbits,” Acta Medica (Hradec Kralove) 40 (1997): 3-8.

[205] S. J. Flora, R. Bhattacharya, and R. Vijayaraghavan, “Combined Therapeutic Potential of Meso-2,3-Dimercaptosuccinic Acid and Calcium Disodium Edetate on the Mobilization and Distribution of Lead in Experimental Lead Intoxication in Rats,” Fundamental and Applied Toxicology 25 (1995): 233-240.

[206] K. Kalia and S. J. Flora, “Strategies for Safe and Effective Therapeutic Measures for Chronic Arsenic and Lead Poisoning,” Journal of Occupational Health 47 (2005): 1-21.

[207] R. F. Kidd, “Results of Dental Amalgam Removal and Mercury Detoxification Using DMPS and Neural Therapy,” Alternative Therapies in Health and Medicine 6 (2000): 49-55.

[208] S. J. Flora and A. Mehta, “Monoisoamyl Dimercaptosuccinic Acid Abrogates Arsenic-Induced Developmental Toxicity in Human Embryonic Stem Cell-Derived Embryoid Bodies: Comparison With in Vivo Studies,” Biochemical Pharmacology 78 (2009): 1340-1349.

[209] M. M. Jones, P. K. Singh, G. R. Gale, A. B. Smith, and L. M. Atkins, “Cadmium Mobilization in Vivo by Intraperitoneal or Oral Administration of Monoalkyl Esters of Meso-2,3-Dimercaptosuccinic Acid in the Mouse,” Pharmacology & Toxicology 70 (1992): 336-343.

[210] A. Mehta, S. C. Pant, and S. J. Flora, “Monoisoamyl Dimercaptosuccinic Acid Induced Changes in Pregnant Female Rats During Late Gestation and Lactation,” Reproductive Toxicology 21 (2006): 94-103.

[211] M. W. Taubeneck, J. L. Domingo, J. M. Llobet, C. L. Keen, “Meso-2,3-Dimercaptosuccinic Acid (DMSA) Affects Maternal and Fetal Copper Metabolism in Swiss Mice,” Toxicology 72 (1992): 27-40.

[212] M. M. Jones, M. A. Basinger, G. R. Gale, L. M. Atkins, A. B. Smith, and A. Stone, “Effect of Chelate Treatments on Kidney, Bone and Brain Lead Levels of Lead-Intoxicated Mice,” Toxicology 89 (1994): 91-100.

[213] S. K. Tandon, S. Singh, and V. K. Jain, “Efficacy of Combined Chelation in Lead Intoxication,” Chemical Research in Toxicology 7 (1994): 585-589.

[214] S. J. Flora, G. M. Kannan, B. P. Pant, and D. K. Jaiswal, “Combined Administration of Oxalic Acid, Succimer and its Analogue for the Reversal of Gallium Arsenide-Induced Oxidative Stress in Rats,” Archives of Toxicology 76 (2002): 269-276.

[215] S. J. Flora, M. Pande, G. M. Kannan, and A. Mehta, “Lead Induced Oxidative Stress and its Recovery Following Co-Administration of Melatonin or N-Acetylcysteine During Chelation With Succimer in Male Rats,” Cellular and Molecular Biology 50 (2004): Ol543-551.

[216] A. Sharma, C. Kshetrimayum, H. G. Sadhu, and S. Kumar, “Arsenic-Induced Oxidative Stress, Cholinesterase Activity in the Brain of Swiss Albino Mice, and its Amelioration by Antioxidants Vitamin E and Coenzyme Q10,” Environmental Science and Pollution Research International 25 (2018): 23946-23953.

[217] V. Eybl, J. Sýkora, J. Koutenský, D. Caisová, A. Schwartz, and F. Mertl, “Interaction of Chelating Agents With cadmium in Mice and Rats,” Environmental Health Perspectives 54 (1984): 267-273.

[218] M. Berlin and S. Ullrebg, “Increased Uptake of Mercury in Mouse Brain Caused by 2,3-Dimercaptopropanol,” Nature 197 (1963): 84-85.

[219] S. M. Suru, “Onion and Garlic Extracts Lessen Cadmium-Induced Nephrotoxicity in Rats,” Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine 21 (2008): 623-633.

[220] S. K. Senapati, S. Dey, S. K. Dwivedi, and D. Swarup, “Effect of Garlic (Allium Sativum L.) Extract on Tissue Lead Level in Rats,” Journal of Ethnopharmacology 76 (2001): 229-232.

[221] M. Aga, K. Iwaki, Y. Ueda, et al., “Preventive Effect of Coriandrum Sativum (Chinese Parsley) on Localized Lead Deposition in ICR Mice,” Journal of Ethnopharmacology 77 (2001): 203-208.

[222] S. Petteruti, “Reduction of Lead Levels in Patients Following a Long-Term, Intermittent Calcium Ethylenediaminetetraacetic Acid (EDTA)-Based Intravenous Chelation Infusions: A Prospective Experimental Cohort,” Cureus 12 (2020): e11685.

[223] S. Bradberry, T. Sheehan, and A. Vale, “Use of Oral Dimercaptosuccinic Acid (Succimer) in Adult Patients With Inorganic Lead Poisoning,” QJM : Monthly Journal of the Association of Physicians 102 (2009): 721-732.

[224] G. Drasch, S. Böse-O'Reilly, C. Beinhoff, G. Roider, and S. Maydl, “The Mt. Diwata Study on the Philippines 1999-Assessing Mercury Intoxication of the Population by Small Scale Gold Mining,” The Science of the Total Environment 267 (2001): 151-168.

[225] S. S. Ali, H. Ahsan, M. K. Zia, T. Siddiqui, and F. H. Khan, “Understanding Oxidants and Antioxidants: Classical Team With New Players,” Journal of Food Biochemistry 44 (2020): e13145.

[226] L. Patrick, “Toxic Metals and Antioxidants: Part II. The Role of Antioxidants in Arsenic and Cadmium Toxicity,” Alternative Medicine Review 8 (2003): 106-128.

[227] Z. Cao, M. Tsang, H. Zhao, and Y. Li, “Induction of Endogenous Antioxidants and Phase 2 Enzymes by α-lipoic Acid in Rat Cardiac H9C2 Cells: Protection Against Oxidative Injury,” Biochemical and Biophysical Research Communications 310 (2003): 979-985.

[228] E. Jiang, X. Chen, Y. Bi, C. Pan, X. Li, and X. Lan, “Curcumin Inhibits Oxidative Stress and Apoptosis Induced by H(2)O(2) in Bovine Adipose-Derived Stem Cells (bADSCs),” Animals 14 (2024): 3421.

[229] A. T. Jan, M. Azam, K. Siddiqui, A. Ali, I. Choi, and Q. M. Haq, “Heavy Metals and Human Health: Mechanistic Insight Into Toxicity and Counter Defense System of Antioxidants,” International Journal of Molecular Sciences 16 (2015): 29592-29630.

[230] J. J. Strain and C. W. Mulholland, “Vitamin C and Vitamin E-Synergistic Interactions in Vivo?” Experientia Supplementum 62 (1992): 419-422.

[231] M. J. Ferreira, T. A. Rodrigues, A. G. Pedrosa, et al., “Glutathione and Peroxisome Redox Homeostasis,” Redox Biology 67 (2023): 102917.

[232] G. Aldini, A. Altomare, G. Baron, et al., “N-Acetylcysteine as an Antioxidant and Disulphide Breaking Agent: The Reasons Why,” Free Radical Research 52 (2018): 751-762.

[233] T. T. Joseph, V. Schuch, D. J. Hossack, R. Chakraborty, and E. L. Johnson, “Melatonin: The Placental Antioxidant and Anti-Inflammatory,” Frontiers in Immunology 15 (2024): 1339304.

[234] I. Pérez-Torres, V. Castrejón-Téllez, M. E. Soto, M. E. Rubio-Ruiz, L. Manzano-Pech, and V. Guarner-Lans, “Oxidative Stress, Plant Natural Antioxidants, and Obesity,” International Journal of Molecular Sciences 22 (2021): 1786.

[235] P. Zhuang, X. Chen, S. Sun, Y. Li, and H. Mo, “Bioaccessibility and Bioavailability of Pb and Cd in Rice is Affected by Propolis and its Extracts and Fe Intervention,” The Science of The Total Environment 951 (2024): 175697.

[236] C. Stanton, G. Gardiner, H. Meehan, et al., “Market Potential for Probiotics,” The American Journal of Clinical Nutrition 73 (2001): 476s-483s.

[237] J. A. Ewe, W. N. Wan-Abdullah, and M. T. Liong, “Viability and Growth Characteristics of Lactobacillus in Soymilk Supplemented With B-Vitamins,” International Journal of Food Sciences and Nutrition 61 (2010): 87-107.

[238] T. Halttunen, S. Salminen, and R. Tahvonen, “Rapid Removal of Lead and Cadmium From Water by Specific Lactic Acid Bacteria,” International Journal of Food Microbiology 114 (2007): 30-35.

[239] A. V. Kirillova, A. A. Danilushkina, D. S. Irisov, et al., “Assessment of Resistance and Bioremediation Ability of Lactobacillus Strains to Lead and Cadmium,” International Journal of Microbiology 2017 (2017): 9869145.

[240] S. Cheng, “Heavy Metal Pollution in China: Origin, Pattern and Control,” Environmental Science and Pollution Research International 10 (2003): 192-198.

[241] V. Singh, G. Ahmed, S. Vedika, et al., “Toxic Heavy Metal Ions Contamination in Water and Their Sustainable Reduction by Eco-Friendly Methods: Isotherms, Thermodynamics and Kinetics Study,” Scientific Reports 14 (2024): 7595.

[242] A. Karnwal, S. Martolia, A. Dohroo, A. Al-Tawaha, and T. Malik, “Exploring Bioremediation Strategies for Heavy Metals and POPs Pollution: The Role of Microbes, Plants, and Nanotechnology,” Frontiers in Environmental Science 12 (2024).

[243] H. Zhang, Y. Xu, T. Kanyerere, Y-s Wang, and M. Sun, “Washing Reagents for Remediating Heavy-Metal-Contaminated Soil: A Review,” Frontiers in Earth Science 10 (2022).

[244] A. Ojha, S. Jaiswal, and P. Thakur, S. K. Mishra, “Bioremediation Techniques for Heavy Metal and Metalloid Removal From Polluted Lands: A Review,” International Journal of Environmental Science and Technology 20 (2023): 10591-10612.

[245] A. M. Shackira, J. T. Puthur: Phytostabilization of Heavy Metals: Understanding of Principles and Practices. Plant-Metal Interactions. In: Edited by Srivastava S, Srivastava AK, Suprasanna P. (Springer International Publishing, 2019): 263-282.

[246] F. S. A. Khan, N. M. Mubarak, M. Khalid, et al., “Magnetic Nanoadsorbents' Potential Route for Heavy Metals Removal-A Review,” Environmental Science and Pollution Research International 27 (2020): 24342-24356.

[247] V. Mohanapriya, R. Sakthivel, N. D. K. Pham, C. K. Cheng, H. S. Le, and T. M. H. Dong, “Nanotechnology- A ray of Hope for Heavy Metals Removal,” Chemosphere 311 (2023): 136989.

[248] M. Samani, Y. K. Ahlawat, and A. Golchin, “Nano Silica-Mediated Stabilization of Heavy Metals in Contaminated Soils,” Scientific Reports 14 (2024): 20496.

[249] Y. S. Alia, I. Shaw, C. Chen, Y. Liu: Perspective Chapter: Advanced Nanotechnology Approach for Heavy Metal Toxicity - Analysis, Treatment, and Removal. Heavy Metals in the Environment—Contamination, Risk, and Remediation. In: Edited by Yoshida M (IntechOpen, 2024).

[250] D. B. Olawade, O. Z. Wada, B. I. Egbewole, et al., “Metal and Metal Oxide Nanomaterials for Heavy Metal Remediation: Novel Approaches for Selective, Regenerative, and Scalable Water Treatment,” Frontiers in Nanotechnology 6 (2024).

[251] W. Xia and M. W. King, “Advances in Targeted Delivery of Doxorubicin for Cancer Chemotherapy,” Bioengineering (Basel) 12 (2025): 430.

[252] Y. Ma, L. Deng, and S. Li, “Application of Nanoparticles in CRISPR/Cas9-Based Gene Therapy,” Sheng Wu Gong Cheng Xue Bao 38 (2022): 2087-2104.

[253] T. Li, Y. Yang, H. Qi, et al., “CRISPR/Cas9 Therapeutics: Progress and Prospects,” Signal Transduction and Targeted Therapy 8 (2023): 36.

[254] M. Kumar, M. R. Prusty, M. K. Pandey, et al., “Application of CRISPR/Cas9-Mediated Gene Editing for Abiotic Stress Management in Crop Plants,” Frontiers in Plant Science 14 (2023): 1157678.

[255] F. Liu, R. Li, Z. Zhu, Y. Yang, and F. Lu, “Current Developments of Gene Therapy in Human Diseases,” MedComm 5 (2024): e645.

[256] H. Mohsin, M. Shafique, M. Zaid, and Y. Rehman, “Microbial Biochemical Pathways of Arsenic Biotransformation and Their Application for Bioremediation,” Folia Microbiologica 68 (2023): 507-535.

[257] N. N. Ramli, A. R. Othman, S. B. Kurniawan, S. R. S. Abdullah, and H. A. Hasan, “Metabolic Pathway of Cr(VI) Reduction by Bacteria: A Review,” Microbiological Research 268 (2023): 127288.

[258] M. H. Hemmat-Jou, S. Liu, Y. Liang, G. Chen, L. Fang, and F. Li, “Microbial Arsenic Methylation in Soil-Water Systems and Its Environmental Significance,”The Science of the Total Environment 944 (2024): 173873.

[259] M. M. Naguib, A. O. El-Gendy, and A. S. Khairalla, “Microbial Diversity of Mer Operon Genes and Their Potential Rules in Mercury Bioremediation and Resistance,” The Open Biotechnology Journal 12 (2018): 56-77.

[260] O. B. Ojuederie and O. O. Babalola, “Microbial and Plant-Assisted Bioremediation of Heavy Metal Polluted Environments: A Review,” International Journal of Environmental Research and Public Health 14 (2017): 1504.

[261] J. Jaroszuk-Ściseł, A. Nowak, M. Pac-Sosińska, D. Kołodyńska, and I. Komaniecka, “Heavy Metal Biosorption Ability of EPS Obtained From Cultures of Fusarium Culmorum Strains With Different Effects on Cereals,” Sustainability 17 (2025): 3744.

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